Important advances have been made in the understanding of the molecular changes associated with the development of melanoma. Oncogenic mutations of B-RAF, a serine-threonine protein kinase in the RAF/MEK/ERK pathway, are particularly common in melanoma, with 40 to 60% of melanoma carrying an activating mutation in the B-Raf gene. The substitution of glutamic acid for valine at amino acid 600 (V600E mutation) represents more than 95% of the reported B-Raf mutations. This mutation constitutively activates B-Raf and downstream signal transduction in the RAF/MEK/ERK pathway, which signals for cancer cell proliferation and survival. In addition to melanoma, such mutations of B-Raf are known to occur in other proliferative diseases, for example, colorectal cancer, thyroid cancer, particularly papillary thyroid cancer, astrocytomas, pancreatic cancer, and neurofibromatosis. Although dramatic results are known to occur when such diseases are treated with a B-Raf inhibitor, the development of resistance to treatment with the B-Raf inhibitor is typical, often occurring within a fairly short period of time.
There are multiple paths to resistance to treatment with a B-Raf inhibitor. The main mechanisms result in reactivation of the RAF/MEK/ERK signaling pathway in the presence of the B-Raf inhibitor. This reactivation can occur via increased activity of receptor tyrosine kinases (RTKs) via gene amplification, and over expression and/or ligand production, acquisition of mutations in the NRAS and MEK1 genes, bypass of BRAF via over-expression of kinases such as COT and RAF-1 (CRAF), expression of splice variants of the mutant BRAF allele, and increased expression of the mutant BRAF allele due to, e.g. gene amplification. In addition, activation of survival pathways such as the PIK3Ca signaling system that are distinct from the MAPK pathway, either via activation of RTKs such as PDGFR-β and IGF-1R or loss of the PTEN gene may also play a role in resistance. Other mechanisms, through c-MET and the FGFR family of RTKs, are potential mechanisms that may promote resistance to B-Raf inhibitors in multiple melanoma.
The findings described above highlight the importance of identifying mechanisms of resistance in real time, in order to initiate a rational combination therapy early on after relapse on B-Raf inhibitor treatment. Using a mechanism-based approach with the comparison of the genetic alterations present in a patient's tumor at the time of relapse versus pre-treatment, it should be possible to identify likely resistance mechanisms. This will help selecting the appropriate drug combination therapy for an individual patient in order to better circumvent resistance. The present invention relates to a mechanism-based combination treatment approach to expand and improve the therapeutic options for patients with BRAF-mutant advanced or metastatic melanoma that have very poor prognosis after the development of resistance to B-Raf inhibitors.